Among the co-morbidities associated with long-term HIV infection, pulmonary arterial hypertension (PAH) remains a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure and right heart failure. Evidence suggests a prominent role for inflammation and autoimmunity in idiopathic PAH, though this concept has been under studied in the context of HIV-PAH. Lack of understanding of the pathogenesis of HIV-PAH, along with deficiencies of available animal models, greatly impede identification and testing of new therapies. We have developed a simian model that closely mimics HIV-PAH. Our preliminary data indicate that inflammation, immunosenescence and autoimmune phenotypes are associated with worse pulmonary hypertension in this model. We therefore hypothesize that the development of HIV-PAH is driven by chronic immune activation and dysregulated immune responses. Additionally, we hypothesize that this dysregulated immune response is driven in part by persistent gut microbial translocation, and contributes to hyper-proliferation of pulmonary arterial smooth muscle cells, vascular tissue damage and fibrosis. Overall goals of this proposal are to improve the understanding of the pathogenesis of HIV-PAH and to use this information to inform the development of adjunctive therapies that will prevent or reverse HIV-PAH. We will test these hypotheses and address these goals by 1) determining the role of chronic immune activation and inflammation on the development of PAH in a non-human primate model of HIV-PAH and 2) examining the effectiveness of anti-retroviral therapy and conventional PAH therapy in this model. We have found that SIV infection is a natural cause of PAH that closely mimics HIV-PAH and we have established multiple modalities of evaluating disease progression, thus we are uniquely positioned to address these goals. The proposed studies will advance our knowledge of disease progression by allowing us to evaluate host immune responses at each stage of the disease process and test efficacy of anti-viral and anti-inflammatory therapies. These studies will not only address the mechanisms associated with the development of HIV-PAH, but they will provide critical information regarding the timing and targets that may be amenable to therapies aimed at both prevention and resolution of vascular damage, hemodynamic alterations and right heart dysfunction.